18 results on '"Conlon, Peter J"'
Search Results
2. Contributors
- Author
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Adler, Sharon, primary, Adrogué, Horacio J., additional, Allon, Michael, additional, Arif-Tiwari, Hina, additional, Arroyo, Vincente, additional, Avery, Robin K., additional, Avila-Casado, Carmen, additional, Barratt, Jonathan, additional, Berns, Jeffrey S., additional, Bomback, Andrew S., additional, Bonventre, Joseph V., additional, Bowling, C. Barrett, additional, Brewster, Ursula C., additional, Briggs, Josephine P., additional, Cattran, Daniel C., additional, Chandran, Sindhu, additional, Chapman, Arlene B., additional, Coca, Steven G., additional, Conlon, Peter J., additional, Copelovitch, Lawrence A., additional, Curhan, Gary, additional, D’Agati, Vivette D., additional, Daoud, Jacques R., additional, de Zeeuw, Dick, additional, Dennen, Paula, additional, Derebail, Vimal K., additional, DuBose, Thomas D., additional, Emmett, Michael, additional, Fairhead, Todd, additional, Falk, Ronald J., additional, Feehally, John, additional, Fernández, Javier, additional, Fervenza, Fernando C., additional, Fioretto, Paola, additional, Födinger, Manuela, additional, Furth, Susan L., additional, Gehr, Todd W.B., additional, Gilbert, Scott J., additional, Gill, Jagbir S., additional, Gipson, Debbie S., additional, Goldstein-Fuchs, D. Jordi, additional, Greenberg, Arthur, additional, Gregory, Martin C., additional, Gunaratnam, Lakshman, additional, Hakim, Raymond M., additional, Hildebrandt, Friedhelm, additional, Hladunewich, Michelle A., additional, Hogan, Jonathan, additional, Hou, Susan, additional, House, Andrew A., additional, Huan, Yonghong, additional, Hutchison, Alastair J., additional, Inker, Lesley A., additional, James, Matthew T., additional, Jayne, David, additional, Jennette, J. Charles, additional, Jiménez, Wladimiro, additional, Kain, Renate, additional, Kalantar-Zadeh, Kamyar, additional, Kalb, Bobby, additional, Knoll, Greg, additional, Kriz, Wilhelm, additional, Tamura, Manjula Kurella, additional, LaPierre, Amy Frances, additional, Lambers Heerspink, Hiddo J., additional, Levey, Andrew S., additional, Lewis, Edmund J., additional, Linas, Stuart L., additional, Macedo, Etienne, additional, Madias, Nicolaos E., additional, Magee, Colm, additional, Mariani, Laura H., additional, Martin, Diego R., additional, Matzke, Gary R., additional, McQuillan, Rory F., additional, Mehrotra, Rajnish, additional, Mehta, Ankit N., additional, Mehta, Ravindra L., additional, Meyers, Catherine M., additional, Meyrier, Alain, additional, Moe, Sharon M., additional, Nast, Cynthia C., additional, Nicolle, Lindsay E., additional, Nolin, Thomas D., additional, O’Hare, Ann M., additional, O’Toole, John F., additional, Pannu, Neesh, additional, Perazella, Mark A., additional, Pusey, Charles D., additional, Quarles, L. Darryl, additional, Radhakrishnan, Jai, additional, Rastegar, Asghar, additional, Redahan, Lynn, additional, Rizk, Dana V., additional, Ronco, Claudio, additional, Rosenblum, Norman D., additional, Salama, Alan D., additional, Sanders, Paul W., additional, Sarnak, Mark J., additional, Scheinman, Steven J., additional, Schnermann, Jurgen B., additional, Semelka, Richard C., additional, Shirali, Anushree, additional, Sica, Domenic A., additional, Sunder-Plassmann, Gere, additional, Sutherland, Richard W., additional, Szerlip, Harold M., additional, Tonelli, Marcello, additional, Townsend, Raymond R., additional, Trachtman, Howard, additional, Turner, Jeffrey M., additional, Vardhan, Anand, additional, Vellanki, Kavitha, additional, Verbalis, Joseph G., additional, Vincenti, Flavio G., additional, Waikar, Sushrut S., additional, Weiner, Daniel E., additional, White, Colin T., additional, Whittier, William L., additional, Wilcox, Christopher S., additional, Wish, Jay B., additional, and Yiu, Vivian, additional
- Published
- 2014
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3. Contributors
- Author
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Adler, Sharon, primary, Adrogué, Horacio J., additional, Aggarwal, Nidhi, additional, Allon, Michael, additional, Anderson, Sharon, additional, Andreoli, Sharon Phillips, additional, Appel, Gerald B., additional, Arroyo, Vicente, additional, August, Phyllis, additional, Bakris, George L., additional, Balow, James E., additional, Beddhu, Srinivasan, additional, Berns, Jeffrey S., additional, Bonventre, Joseph V., additional, Braga, Larissa, additional, Briggs, Josephine P., additional, Caramori, Maria Luiza, additional, Cattran, Daniel C., additional, Chapman, Arlene B., additional, Chertow, Glenn M., additional, Cheung, Alfred K., additional, Cho, Kerry C., additional, Coffman, Thomas M., additional, Conlon, Peter J., additional, Connaire, Jeffrey J., additional, Curhan, Gary, additional, Dennen, Paula, additional, DuBose, Thomas D., additional, Ellison, David H., additional, Emmett, Michael, additional, Falk, Ronald J., additional, Fernández, Javier, additional, Goeddeke-Merickel, Catherine M., additional, Goldstein-Fuchs, D. Jordi, additional, Greenberg, Arthur, additional, Gregory, Martin C., additional, Guasch, Antonio, additional, Gunaratnam, Lakshman, additional, Henrich, William L., additional, Hildebrandt, Friedhelm, additional, Hogg, Ronald J., additional, Holley, Jean L., additional, Hsu, Chi-yuan, additional, Hutchison, Alastair J., additional, Jayne, A. David, additional, Jennette, J. Charles, additional, Jiménez, Wladimiro, additional, Kasiske, Bertram L., additional, Khosla, Nitin, additional, Klotman, Paul E., additional, Kovalik, Eugene C., additional, Kovalik, Jean-Paul, additional, Krause, Michelle Whittier, additional, Kriz, Wilhelm, additional, Levey, Andrew S., additional, Lin, Fang-Ying, additional, Linas, Stuart, additional, Madias, Nicolaos E., additional, Mannon, Roslyn B., additional, Martin, Diego R., additional, MatzkePharmD, Gary R., additional, Maver, Michael, additional, McQuillan, Rory, additional, Mehta, Ankit N., additional, Meyers, Catherine M., additional, Meyrier, Alain, additional, Moe, Sharon M., additional, Monahan, Marianne, additional, Murali, Narayana S., additional, Nast, Cynthia C., additional, Nath, Karl A., additional, Nicolle, Lindsay E., additional, O'Toole, John F., additional, Palmer, Biff F., additional, Pisoni, Roberto, additional, Podymow, Tiina, additional, Pusey, Charles D., additional, Quarles, L. Darryl, additional, Rao, Maya K., additional, Remuzzi, Giuseppe, additional, Ritz, Eberhard, additional, Saifullah, Akber, additional, Salama, Alan D., additional, Sanders, Paul W., additional, Sarnak, Mark J., additional, Scheinman, Steven J., additional, Schieppati, Arrigo, additional, Schnermann, Jürgen B., additional, Semelka, Richard C., additional, Stevens, Lesley A., additional, Stoycheff, Nicholas, additional, Szerlip, Harold M., additional, Tanenbaum, Nadine D., additional, Trachtman, Howard, additional, Verbalis, Joseph G., additional, Vardhan, Anand, additional, Weiner, Daniel E., additional, Wilcox, Christopher S., additional, Wish, Jay B., additional, Wyatt, Christina M., additional, and Ziyadeh, Fuad N., additional
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- 2009
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4. A Novel Monoallelic ALG5 Variant Causing Late-Onset ADPKD and Tubulointerstitial Fibrosis.
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Elhassan EAE, Kmochová T, Benson KA, Fennelly NK, Barešová V, Kidd K, Doyle B, Dorman A, Morrin MM, Kyne NC, Vyleťal P, Hartmannová H, Hodaňová K, Sovová J, Mušálková D, Vrbacká A, Přistoupilová A, Živný J, Svojšová K, Radina M, Stránecký V, Loginov D, Pompach P, Novák P, Vaníčková Z, Hansíková H, Rajnochová-Bloudíčková S, Viklický O, Hůlková H, Cavalleri GL, Hnízda A, Bleyer AJ, Kmoch S, Conlon PJ, and Živná M
- Abstract
Introduction: Monoallelic variants in the ALG5 gene encoding asparagine-linked glycosylation protein 5 homolog (ALG5) have been recently shown to disrupt polycystin-1 (PC1) maturation and trafficking via underglycosylation, causing an autosomal dominant polycystic kidney disease-like (ADPKD-like) phenotype and interstitial fibrosis. In this report, we present clinical, genetic, histopathologic, and protein structure and functional correlates of a new ALG5 variant, p.R79W, that we identified in 2 distant genetically related Irish families displaying an atypical late-onset ADPKD phenotype combined with tubulointerstitial damage., Methods: Whole exome and targeted sequencing were used for segregation analysis of available relatives. This was followed by immunohistochemistry examinations of kidney biopsies, and targeted (UMOD, MUC1) and untargeted plasma proteome and N-glycomic studies., Results: We identified a monoallelic ALG5 variant [GRCh37 (NM_013338.5): g.37569565G>A, c.235C>T; p.R79W] that cosegregates in 23 individuals, of whom 18 were clinically affected. We detected abnormal localization of ALG5 in the Golgi apparatus of renal tubular cells in patients' kidney specimens. Further, we detected the pathological accumulation of uromodulin, an N-glycosylated glycosylphosphatidylinositol (GPI)-anchored protein, in the endoplasmic reticulum (ER), but not mucin-1, an O- and N-glycosylated protein. Biochemical investigation revealed decreased plasma and urinary uromodulin levels in clinically affected individuals. Proteomic and glycoproteomic profiling revealed the dysregulation of chronic kidney disease (CKD)-associated proteins., Conclusion: ALG5 dysfunction adversely affects maturation and trafficking of N-glycosylated and GPI anchored protein uromodulin, leading to structural and functional changes in the kidney. Our findings confirm ALG5 as a cause of late-onset ADPKD and provide additional insight into the molecular mechanisms of ADPKD- ALG5 ., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)
- Published
- 2024
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5. Familial Variability of Disease Severity in Adult Patients With ADPKD.
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Elhassan EAE, O'Kelly P, Collins KE, Teltsh O, Ciurli F, Murray SL, Kennedy C, Madden SF, Benson KA, Cavalleri GL, and Conlon PJ
- Abstract
Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic nephropathy and has striking familial variability of disease severity., Methods: To better comprehend familial phenotypic variability, we analyzed clinical and pedigree data on 92 unrelated ADPKD kindreds with ≥2 affected individuals ( N = 292) from an Irish population. All probands underwent genetic sequencing. Age at onset of kidney failure (KF), decline in estimated glomerular filtration rate (eGFR), predicting renal outcome in polycystic kidney disease (PROPKD) score, and imaging criteria were used to assess and grade disease severity as mild, intermediate, or severe. One mild and 1 severe case per family defined marked intrafamilial variability of disease severity., Results: Marked intrafamilial variability was observed in at least 13% of the 92 families, with a higher proportion of families carrying PKD1 -nontruncating ( PKD1 -NT) variants. In families with ≥2 members affected by KF, the average intrafamilial age difference was 7 years, and there was no observed difference in intrafamilial variability of age at KF between allelic groups. The prespecified criteria showed marked familial variability in 7.7%, 8.4%, and 24% for age at KF, the PROPKD score, and imaging criteria, respectively. In our multivariate mixed-effects model, the intrafamilial variability in kidney survival was independent of the measured genotypic factors associated with prognosis and survival ( P = <0.001)., Conclusion: Using objective measures, we quantified marked intrafamilial variability in ADPKD disease phenotype in at least 13% of families. Our findings indicate that intrafamilial phenotypic variability remains incompletely understood and necessitates a more thorough identification of relevant clinical and genotypic factors., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)
- Published
- 2023
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6. Persistent DNA damage underlies tubular cell polyploidization and progression to chronic kidney disease in kidneys deficient in the DNA repair protein FAN1.
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Airik M, Phua YL, Huynh AB, McCourt BT, Rush BM, Tan RJ, Vockley J, Murray SL, Dorman A, Conlon PJ, and Airik R
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- Animals, Humans, Mice, DNA Damage, DNA Repair, Endodeoxyribonucleases genetics, Endodeoxyribonucleases metabolism, Exodeoxyribonucleases genetics, Exodeoxyribonucleases metabolism, Fibrosis, Kidney pathology, Mice, Knockout, Multifunctional Enzymes genetics, Multifunctional Enzymes metabolism, Roscovitine, Nephritis, Interstitial pathology, Renal Insufficiency, Chronic etiology
- Abstract
Defective DNA repair pathways contribute to the development of chronic kidney disease (CKD) in humans. However, the molecular mechanisms underlying DNA damage-induced CKD pathogenesis are not well understood. Here, we investigated the role of tubular cell DNA damage in the pathogenesis of CKD using mice in which the DNA repair protein Fan1 was knocked out. The phenotype of these mice is orthologous to the human DNA damage syndrome, karyomegalic interstitial nephritis (KIN). Inactivation of Fan1 in kidney proximal tubule cells sensitized the kidneys to genotoxic and obstructive injury characterized by replication stress and persistent DNA damage response activity. Accumulation of DNA damage in Fan1 tubular cells induced epithelial dedifferentiation and tubular injury. Characteristic to KIN, cells with chronic DNA damage failed to complete mitosis and underwent polyploidization. In vitro and in vivo studies showed that polyploidization was caused by the overexpression of DNA replication factors CDT1 and CDC6 in FAN1 deficient cells. Mechanistically, inhibiting DNA replication with Roscovitine reduced tubular injury, blocked the development of KIN and mitigated kidney function in these Fan1 knockout mice. Thus, our data delineate a mechanistic pathway by which persistent DNA damage in the kidney tubular cells leads to kidney injury and development of CKD. Furthermore, therapeutic modulation of cell cycle activity may provide an opportunity to mitigate the DNA damage response induced CKD progression., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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7. Pilot Randomized Controlled Trial of a Standard Versus a Modified Low-Phosphorus Diet in Hemodialysis Patients.
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Byrne FN, Gillman BA, Kiely M, Palmer B, Shiely F, Kearney PM, Earlie J, Bowles MB, Keohane FM, Connolly PP, Wade S, Rennick TA, Moore BL, Smith ON, Sands CM, Slevin O, McCarthy DC, Brennan KM, Mellett H, Dahly D, Bergin E, Casserly LF, Conlon PJ, Hannan K, Holian J, Lappin DW, O'Meara YM, Mellotte GJ, Reddan D, Watson A, and Eustace J
- Abstract
Introduction: The standard low-phosphorus diet restricts pulses, nuts, and whole grains and other high phosphorus foods to control hyperphosphatemia. We conducted a randomized controlled trial to evaluate the effectiveness, safety, and tolerability of the modified diet, which introduced some pulses and nuts, increased the use of whole grains, increased focus on the avoidance of phosphate additives, and introduced the prescription of low-biological-value protein such as bread., Methods: We conducted a multicenter, pragmatic, parallel-arm, open-label, randomized controlled trial of modified versus standard diet in 74 adults on hemodialysis with hyperphosphatemia over 1 month. Biochemistry was assessed using monthly laboratory tests. Dietary intake was assessed using a 2-day record of weighed intake of food, and tolerability was assessed using a patient questionnaire., Results: There was no significant difference in the change in serum phosphate between the standard and modified diets. Although total dietary phosphorus intake was similar, phytate-bound phosphorus, found in pulses, nuts, and whole grains, was significantly higher in the modified diet ( P < 0.001). Dietary fiber intake was also significantly higher ( P < 0.003), as was the percentage of patients reporting an increase in bowel movements while following the modified diet ( P = 0.008). There was no significant difference in the change in serum potassium or in reported protein intake between the 2 diets. Both diets were similarly well tolerated., Conclusion: The modified low phosphorus diet was well tolerated and was associated with similar phosphate and potassium control but with a wider food choice and greater fiber intake than the standard diet., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)
- Published
- 2020
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8. Genetic and Clinical Predictors of Age of ESKD in Individuals With Autosomal Dominant Tubulointerstitial Kidney Disease Due to UMOD Mutations.
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Kidd K, Vylet'al P, Schaeffer C, Olinger E, Živná M, Hodaňová K, Robins V, Johnson E, Taylor A, Martin L, Izzi C, Jorge SC, Calado J, Torres RJ, Lhotta K, Steubl D, Gale DP, Gast C, Gombos E, Ainsworth HC, Chen YM, Almeida JR, de Souza CF, Silveira C, Raposeiro R, Weller N, Conlon PJ, Murray SL, Benson KA, Cavalleri GL, Votruba M, Vrbacká A, Amoroso A, Gianchino D, Caridi G, Ghiggeri GM, Divers J, Scolari F, Devuyst O, Rampoldi L, Kmoch S, and Bleyer AJ
- Abstract
Introduction: Autosomal dominant tubulo-interstitial kidney disease due to UMOD mutations (ADTKD- UMOD ) is a rare condition associated with high variability in the age of end-stage kidney disease (ESKD). The minor allele of rs4293393, located in the promoter of the UMOD gene, is present in 19% of the population and downregulates uromodulin production by approximately 50% and might affect the age of ESKD. The goal of this study was to better understand the genetic and clinical characteristics of ADTKD- UMOD and to perform a Mendelian randomization study to determine if the minor allele of rs4293393 was associated with better kidney survival., Methods: An international group of collaborators collected clinical and genetic data on 722 affected individuals from 249 families with 125 mutations, including 28 new mutations. The median age of ESKD was 47 years. Men were at a much higher risk of progression to ESKD (hazard ratio 1.78, P < 0.001)., Results: The allele frequency of the minor rs4293393 allele was only 11.6% versus the 19% expected ( P < 0.01), resulting in Hardy-Weinberg disequilibrium and precluding a Mendelian randomization experiment. An in vitro score reflecting the severity of the trafficking defect of uromodulin mutants was found to be a promising predictor of the age of ESKD., Conclusion: We report the clinical characteristics associated with 125 UMOD mutations. Male gender and a new in vitro score predict age of ESKD., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)
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- 2020
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9. Neutrophil gelatinase-associated lipocalin (NGAL) is localised to the primary cilium in renal tubular epithelial cells - A novel source of urinary biomarkers of renal injury.
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Cassidy H, Slyne J, Higgins M, Radford R, Conlon PJ, Watson AJ, Ryan MP, McMorrow T, and Slattery C
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- ADP-Ribosylation Factors analysis, ADP-Ribosylation Factors urine, Biomarkers analysis, Cell Line, Cilia chemistry, Epithelial Cells cytology, Humans, Kidney Diseases pathology, Kidney Diseases urine, Kidney Tubules cytology, Lipocalin-2 urine, Cilia pathology, Epithelial Cells pathology, Kidney Diseases diagnosis, Kidney Tubules pathology, Lipocalin-2 analysis
- Abstract
Background: Primary cilia have been shown to play a central role in regulating epithelial cell differentiation during injury and repair. Growing evidence implicates structural and functional abnormalities of primary cilia in kidney epithelial cells in the onset and development of various kidney diseases including polycystic kidney disease (PKD). Neutrophil-gelatinase associated lipocalin (NGAL) has been identified as a reliable urinary biomarker of kidney injury. However, the mechanism by which this protein accumulates in patient urine samples has not been fully elucidated., Methods: Human renal tubular epithelial cells (RPTECs) were exposed to previously characterized deciliating agents to assess mechanisms of primary cilium loss. Confocal immunofluorescent imaging was employed to visualise the effects on cilia. Western blot analysis was utilised to quantify the ciliary protein Arl13b in both RPTEC whole cell lysates and supernatants. Co-immunoprecipitation was used to demonstrate co-localisation of Arl13b and NGAL in urinary samples from a clinical Chronic Allograft Nephropathy (CAN) cohort., Results: Immunofluorescent analysis revealed that NGAL was localised to the primary cilium in RPTECs, co-localizing with a ciliary specific protein, Arl13b. Deciliation experiments showed that loss of the cilia coincided with loss of NGAL from the cells., Conclusion: The accumulation of NGAL in supernatants in vitro and in the urine of CAN patients was concurrent with loss of Arl13b, a specific ciliary protein. The findings of this study propose that increased NGAL urinary concentrations are directly linked to deciliation of the renal epithelial cells as a result of injury., (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Published
- 2019
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10. The impact of donor and recipient common clinical and genetic variation on estimated glomerular filtration rate in a European renal transplant population.
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Stapleton CP, Heinzel A, Guan W, van der Most PJ, van Setten J, Lord GM, Keating BJ, Israni AK, de Borst MH, Bakker SJL, Snieder H, Weale ME, Delaney F, Hernandez-Fuentes MP, Reindl-Schwaighofer R, Oberbauer R, Jacobson PA, Mark PB, Chapman FA, Phelan PJ, Kennedy C, Sexton D, Murray S, Jardine A, Traynor JP, McKnight AJ, Maxwell AP, Smyth LJ, Oetting WS, Matas AJ, Mannon RB, Schladt DP, Iklé DN, Cavalleri GL, and Conlon PJ
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- Adult, Europe epidemiology, Female, Follow-Up Studies, Genome-Wide Association Study, Glomerular Filtration Rate, Graft Rejection epidemiology, Graft Rejection genetics, Graft Survival, Humans, Kidney Failure, Chronic genetics, Kidney Failure, Chronic surgery, Kidney Function Tests, Living Donors statistics & numerical data, Male, Middle Aged, Postoperative Complications epidemiology, Postoperative Complications genetics, Prognosis, Retrospective Studies, Risk Factors, Transplant Recipients statistics & numerical data, Genetic Markers, Genetic Variation, Graft Rejection diagnosis, Kidney physiopathology, Kidney Transplantation adverse effects, Postoperative Complications diagnosis, Risk Assessment methods
- Abstract
Genetic variation across the human leukocyte antigen loci is known to influence renal-transplant outcome. However, the impact of genetic variation beyond the human leukocyte antigen loci is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with posttransplant eGFR at different time-points, out to 5 years posttransplantation. We conducted GWAS meta-analyses across 10 844 donors and recipients from five European ancestry cohorts. We also analyzed the impact of polygenic risk scores (PRS), calculated using genetic variants associated with nontransplant eGFR, on posttransplant eGFR. PRS calculated using the recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with eGFR at 1-year posttransplant. Thirty-two percent of the variability in eGFR at 1-year posttransplant was explained by our model containing clinical covariates (including weights for death/graft-failure), principal components and combined donor-recipient PRS, with 0.3% contributed by the PRS. No individual genetic variant was significantly associated with eGFR posttransplant in the GWAS. This is the first study to examine PRS, composed of variants that impact kidney function in the general population, in a posttransplant context. Despite PRS being a significant predictor of eGFR posttransplant, the effect size of common genetic factors is limited compared to clinical variables., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)
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- 2019
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11. Monogenic causes of chronic kidney disease in adults.
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Connaughton DM, Kennedy C, Shril S, Mann N, Murray SL, Williams PA, Conlon E, Nakayama M, van der Ven AT, Ityel H, Kause F, Kolvenbach CM, Dai R, Vivante A, Braun DA, Schneider R, Kitzler TM, Moloney B, Moran CP, Smyth JS, Kennedy A, Benson K, Stapleton C, Denton M, Magee C, O'Seaghdha CM, Plant WD, Griffin MD, Awan A, Sweeney C, Mane SM, Lifton RP, Griffin B, Leavey S, Casserly L, de Freitas DG, Holian J, Dorman A, Doyle B, Lavin PJ, Little MA, Conlon PJ, and Hildebrandt F
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- Adolescent, Adult, Age of Onset, Aged, Aged, 80 and over, Cohort Studies, Exome genetics, Female, Humans, Ireland, Kidney, Male, Medical History Taking, Middle Aged, Mutation, Pedigree, Precision Medicine, Renal Insufficiency, Chronic diagnosis, Renal Insufficiency, Chronic therapy, Young Adult, Genetic Predisposition to Disease, Genetic Testing methods, Renal Insufficiency, Chronic genetics, Exome Sequencing
- Abstract
Approximately 500 monogenic causes of chronic kidney disease (CKD) have been identified, mainly in pediatric populations. The frequency of monogenic causes among adults with CKD has been less extensively studied. To determine the likelihood of detecting monogenic causes of CKD in adults presenting to nephrology services in Ireland, we conducted whole exome sequencing (WES) in a multi-centre cohort of 114 families including 138 affected individuals with CKD. Affected adults were recruited from 78 families with a positive family history, 16 families with extra-renal features, and 20 families with neither a family history nor extra-renal features. We detected a pathogenic mutation in a known CKD gene in 42 of 114 families (37%). A monogenic cause was identified in 36% of affected families with a positive family history of CKD, 69% of those with extra-renal features, and only 15% of those without a family history or extra-renal features. There was no difference in the rate of genetic diagnosis in individuals with childhood versus adult onset CKD. Among the 42 families in whom a monogenic cause was identified, WES confirmed the clinical diagnosis in 17 (40%), corrected the clinical diagnosis in 9 (22%), and established a diagnosis for the first time in 16 families referred with CKD of unknown etiology (38%). In this multi-centre study of adults with CKD, a molecular genetic diagnosis was established in over one-third of families. In the evolving era of precision medicine, WES may be an important tool to identify the cause of CKD in adults., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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12. Polygenic risk score as a determinant of risk of non-melanoma skin cancer in a European-descent renal transplant cohort.
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Stapleton CP, Birdwell KA, McKnight AJ, Maxwell AP, Mark PB, Sanders ML, Chapman FA, van Setten J, Phelan PJ, Kennedy C, Jardine A, Traynor JP, Keating B, Conlon PJ, and Cavalleri GL
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- Carcinoma, Basal Cell diagnosis, Carcinoma, Basal Cell epidemiology, Carcinoma, Basal Cell etiology, Carcinoma, Squamous Cell diagnosis, Carcinoma, Squamous Cell epidemiology, Carcinoma, Squamous Cell etiology, Case-Control Studies, Cohort Studies, Female, Follow-Up Studies, Genome-Wide Association Study, Humans, Incidence, Male, Middle Aged, Postoperative Complications epidemiology, Postoperative Complications etiology, Prognosis, Risk Factors, Skin Neoplasms epidemiology, Skin Neoplasms etiology, Transplant Recipients, United States epidemiology, Biomarkers, Tumor genetics, Kidney Failure, Chronic surgery, Kidney Transplantation adverse effects, Polymorphism, Single Nucleotide, Postoperative Complications diagnosis, Skin Neoplasms diagnosis
- Abstract
Renal transplant recipients have an increased risk of non-melanoma skin cancer (NMSC) compared to in the general population. Here, we show polygenic risk scores (PRS) calculated from genome-wide association studies (GWAS) of NMSC in a general, nontransplant setting, can predict risk of, and time to posttransplant skin cancer. Genetic variants, reaching predefined P-value thresholds were chosen from published squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) nontransplant GWAS. Using these GWAS, BCC and SCC PRS were calculated for each sample across three European ancestry renal transplant cohorts (n = 889) and tested as predictors of case:control status and time to NMSC posttransplant. BCC PRS calculated at P-value threshold 1 × 10
-5 was the most significant predictor of case:control status of NMSC posttransplant (OR = 1.61; adjusted P = .0022; AUC [full model adjusted for clinical predictors and PRS] = 0.81). SCC PRS at P-value threshold 1 × 10-5 was the most significant predictor of time to posttransplant NMSC (adjusted P = 9.39 × 10-7 ; HR = 1.41, concordance [full model] = 0.74). PRS of nontransplant NMSC is predictive of case:control status and time to NMSC posttransplant. These results are relevant to how genomics can risk stratify patients to help develop personalized treatment regimens., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)- Published
- 2019
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13. Direct-Acting Oral Anticoagulants as Prophylaxis Against Thromboembolism in the Nephrotic Syndrome.
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Sexton DJ, de Freitas DG, Little MA, McHugh T, Magee C, Conlon PJ, and O'Seaghdha CM
- Abstract
We report 2 cases of apixaban use as prophylaxis against thromboembolism in the nephrotic syndrome (NS), and review the existing literature on direct-acting oral anticoagulant (DOAC) use in this scenario. Our cases appear to be the first reported use of apixaban as prophylaxis against thromboembolism in NS. We report our systematic review of the existing literature on direct-acting oral anticoagulant (DOAC) use in NS, and discuss theoretical issues relevant to their therapeutic use in this clinical scenario. We searched electronic databases such as OVID, EMBASE, PubMed, and CENTRAL, DARE. The search to identify studies and the application of inclusion and exclusion criteria was performed in duplicate independently. We identified 1 pilot randomized study, 3 case reports, and 3 conference proceedings abstracts relating to DOAC use in NS. These reports all pertain to the treatment of clinically evident thrombosis in NS with rivaroxaban, edoxaban, and dabigatran rather than prophylaxis against thrombosis. Although the existing literature on DOAC use in NS is limited, initial preliminary experience appears promising.
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- 2018
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14. Understanding What Influences the Health-Related Quality of Life of Hemodialysis Patients: A Collaborative Study in England and Ireland.
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Lowney AC, Myles HT, Bristowe K, Lowney EL, Shepherd K, Murphy M, O'Brien T, Casserly L, McQuillan R, Plant WD, Conlon PJ, Vinen C, Eustace JA, and Murtagh FE
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- Aged, Cost of Illness, Cross-Sectional Studies, England epidemiology, Female, Humans, Ireland epidemiology, Kidney Failure, Chronic mortality, Kidney Failure, Chronic physiopathology, Male, Middle Aged, Pain mortality, Pain physiopathology, Pain psychology, Palliative Care psychology, Psychological Tests, Regression Analysis, Severity of Illness Index, Kidney Failure, Chronic psychology, Kidney Failure, Chronic therapy, Quality of Life, Renal Dialysis psychology
- Abstract
Context: The international cohort of hemodialysis patients is aging and increasing in number. Nephrologists have a therapeutic relationship with their patients that may span decades. Often overlooked components of chronic disease management include symptom control and assessment of health-related quality of life (HRQoL)., Objectives: This study describes the symptom profile of a large cohort of patients with end-stage renal disease on hemodialysis in England and Ireland and evaluates how symptom burden and other factors influence quality-of-life scores., Methods: A prospective cross-sectional observational study of hemodialysis patients was conducted in Ireland and England during 2011 and 2012. Two validated clinical tools were used to determine HRQoL and symptom burden. Demographic and clinical data were examined, and regression analysis was used to determine associations with HRQoL scores., Results: A total of 893 patients on hemodialysis (mean [SD] age 64 [16] years) had a high symptom burden and poor HRQoL compared with population norms. Specifically, 64% of patients reported pain (95% confidence interval 61%-67%) and 79% reported weakness (95% confidence interval 75%-81%). A total of 43 percent of patients reported between six and 10 symptoms in the week preceding the survey. HRQoL was significantly and independently associated with poor mobility and pain and remained significant after adjusting for variations in clinical characteristics. Being listed on a transplant wait-list register was positively associated with HRQoL., Conclusion: These findings illustrate the high symptom burden and poor HRQoL of the hemodialysis population. Emphasis during clinical reviews on pain assessment and on assessing mobility plus interventions, such as pain management and physiotherapy/occupational therapy, are practical ways for renal teams to help improve patients' quality of life., (Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
15. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis.
- Author
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Malone AF, Phelan PJ, Hall G, Cetincelik U, Homstad A, Alonso AS, Jiang R, Lindsey TB, Wu G, Sparks MA, Smith SR, Webb NJ, Kalra PA, Adeyemo AA, Shaw AS, Conlon PJ, Jennette JC, Howell DN, Winn MP, and Gbadegesin RA
- Subjects
- Adolescent, Adult, Child, DNA Mutational Analysis, Exome, Female, Genetic Testing, Genotype, Glomerular Basement Membrane ultrastructure, Glomerulosclerosis, Focal Segmental complications, Glomerulosclerosis, Focal Segmental pathology, Hearing Loss genetics, Hematuria etiology, Humans, Male, Middle Aged, Mutation, Missense, Phenotype, Podocytes ultrastructure, Proteinuria etiology, Young Adult, Autoantigens genetics, Collagen Type IV genetics, Glomerulosclerosis, Focal Segmental genetics
- Abstract
Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes, including inherited genetic defects, with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome (AS), thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane (GBM) findings. Secondary FSGS is known to develop in classic AS at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical finding at diagnosis was proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic-range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin GBM, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes.
- Published
- 2014
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16. A comparison of long-term graft survival rates between the first and second donor kidney transplanted--the effect of a longer cold ischaemic time for the second kidney.
- Author
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Giblin L, O'Kelly P, Little D, Hickey D, Donohue J, Walshe JJ, Spencer S, and Conlon PJ
- Subjects
- Adult, Cold Temperature, Cyclosporine pharmacology, Female, Humans, Immunosuppressive Agents pharmacology, Ischemia, Male, Middle Aged, Risk Factors, Time Factors, Tissue Donors, Treatment Outcome, Graft Survival, Kidney Transplantation methods, Organ Preservation methods
- Abstract
Prolonged cold ischaemic time (CIT) is associated with delayed initial graft function and may also have a negative impact on long-term graft outcome. We carried out a study comparing the long-term graft survival rates between those recipients who received the first of a pair of donor kidneys versus the recipient of the second graft. Adult kidney transplant recipients who received one of a pair of donor kidneys at our institution between 1989-1995 were included. All recipients received a cyclosporin based immunosupression regimen. Graft survival rates were compared between the 2 groups at 1-, 3-, 5- and 10-year intervals. A total of 520 renal transplant grafts were included in this study. Mean donor age was 35.4 years. Groups were similar for recipient age, gender, number of HLA mismatches, transplant number for that patient and percentage PRA. CIT was the only variable that was significantly different between the two groups; mean of 19.93 h in the first group compared to 25.65 h in the second group. Graft survival rates for the first kidney were significantly better than the second kidney-graft survival at 1 year 88.5% versus 84.7%, at 3 years 81.8% versus 76.7%, at 5 years 72.2% versus 64.9% and at 10 years 55.2% versus 40% (p = 0.012). Patient survival rates were similar in both groups. In our experience, the long-term graft survival rates are significantly better for the first kidney transplanted compared to the second kidney.
- Published
- 2005
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17. The association of lowest hematocrit during cardiopulmonary bypass with acute renal injury after coronary artery bypass surgery.
- Author
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Swaminathan M, Phillips-Bute BG, Conlon PJ, Smith PK, Newman MF, and Stafford-Smith M
- Subjects
- Acute Disease, Female, Humans, Male, Middle Aged, Multivariate Analysis, Regression Analysis, Cardiopulmonary Bypass, Coronary Artery Bypass adverse effects, Hematocrit statistics & numerical data, Intraoperative Care, Kidney Diseases etiology
- Abstract
Background: Acute renal injury is a common serious complication of cardiac surgery. Moderate hemodilution is thought to reduce the risk of kidney injury but the current practice of extreme hemodilution (target hematocrit 22% to 24%) during cardiopulmonary bypass (CPB) has been linked to adverse outcomes after cardiac surgery. Therefore we tested the hypothesis that lowest hematocrit during CPB is independently associated with acute renal injury after cardiac surgery., Methods: Demographic, perioperative, and laboratory data were gathered for 1,404 primary elective coronary bypass surgery patients. Preoperative and daily postoperative creatinine values were measured until hospital discharge per institutional protocol. Stepwise multivariable linear regression analysis was performed to determine whether lowest hematocrit during CPB was independently associated with peak fractional change in creatinine (defined as the difference between the preoperative and peak postoperative creatinine represented as a percentage of the preoperative value). A p value of less than 0.05 was considered significant., Results: Multivariable analyses including preoperative hematocrit and other perioperative variables revealed that lowest hematocrit during CPB demonstrated a significant interaction with body weight and was highly associated with peak fractional change in serum creatinine (parameter estimate [PE] = 4.5; p = 0.008) and also with highest postoperative creatinine value (PE = 0.06; p = 0.004). Although other renal risk factors were significant covariates in both models, TM50 (an index of hypotension during CPB) was notably absent., Conclusions: These results add to concerns that current CPB management guidelines accepting extreme hemodilution may contribute to postoperative acute renal and other organ injury after cardiac surgery.
- Published
- 2003
- Full Text
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18. The effect of pre-existing ischaemic heart disease on renal dysfunction in cardiac transplant recipients.
- Author
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Abraham KA, McGorrian C, O'Kelly P, Neligan M, Woods AE, Conlon PJ, and Donohoe J
- Subjects
- Adolescent, Adult, Age Factors, Aged, Child, Creatinine blood, Female, Humans, Male, Middle Aged, Risk Factors, Sex Characteristics, Survival Rate, Time Factors, Heart Transplantation, Kidney Diseases complications, Kidney Diseases etiology, Myocardial Ischemia complications, Myocardial Ischemia surgery
- Abstract
Renal dysfunction is a recognized complication of cardiac transplantation and can impact on the life expectancy of an already fragile population. A large proportion of these patients require transplantation because of the consequences of ischaemic heart disease (IHD) which, in turn, is often associated with ischaemic nephropathy. We studied the effect of IHD, diagnosed prior to transplantation, on the renal function of recipients who survived more than 6months after surgery. Of the 168 patients transplanted in a single centre over 15 years, 132 were included in the study. Renal dysfunction was defined as a serum creatinine consistently above 200 micromol/L (2.26 mg/dL). Analysis confirmed that IHD was an independent risk factor for developing renal impairment. In transplant recipients with IHD, closer monitoring is warranted to detect and prevent renal dysfunction or to retard its progression.
- Published
- 2002
- Full Text
- View/download PDF
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